Acalabrutinib is a Bruton tyrosine kinase inhibitor (BTKi) approved for use in the treatment of chronic lymphocytic leukemia (CLL). Herein, we present a patient successfully treated with reduced-dose acalabrutinib for CLL, with pre-existing hypogammaglobulinemia-type immunoglobulin G (IgG) and immunoglobulin M (IgM). Here, CD40LG is linked to B-cell chronic lymphocytic leukemia.